Introduction

Glioblastoma multiforme is the most common primary malignant brain tumor in adults and carries a median survival of less than 1 year.

The current standard of care consists of surgical resection followed by radiotherapy.

Although carmustine is commonly prescribed in the United States, no randomized phase III trial of nitrosourea-based chemotherapy has demonstrated a survival benefit compared to radiation alone.

Temozolomide has demonstrated activity in the treatment of recurrent glioma, and a pilot phase II trial of concomitant temozolomide and radiation therapy followed by adjuvant temozolomide showed promising results.

Methods

Eligible patients included those aged 18 to 70 years with newly diagnosed and histologically confirmed glioblastoma multiforme, and a WHO performance status of 2 or less.

Those patients on corticosteroids were eligible only if the dose was stable or decreasing for at least 14 days prior to randomization.

Study participants were stratified according to WHO performance status, whether or not they had undergone a debulking surgical procedure, and treatment center.

Radiation consisted of 2 Gy daily fractions (Monday through Friday) for a total dose of 60 Gy delivered to the gross tumor volume with a 2 to 3 cm margin.

Concomitant temozolomide was given 7 days a week at a dose of 75 mg per square meter body surface area.

Adjuvant temozolomide was given for 5 days, followed by a 23-day break, and then was continued for up to six cycles. The first cycle began 4 weeks after the end of radiation treatment at a dose of 150 mg per square meter body surface area; subsequent doses were increased to 200 mg per square meter body surface area, provided there were no hematologic toxic effects.

Tumor progression was defined as: an increase in tumor size by 25 percent, the appearance of new lesions, or an increased need for corticosteroids.

The primary end point was overall survival, and secondary end points were progression-free survival, safety, and quality of life

Analyses were conducted on an intention-to-treat basis, and the study was powered at 80 percent at a 5 percent significance level to detect a 33 percent increase in median survival.

Results

573 patients from 85 institutions in 15 countries were randomized between August 2000 and March 2002

The median age was 56 years

84 percent of patients underwent debulking surgery

Median follow-up was 28 months

Slightly more patients in the radiotherapy alone group were receiving corticosteroids at the time of randomization

The hazard ratio for death was 0.63 (p<0.001) and for death or disease progression was 0.54 (p<0.001) in the temozolomide group versus the radiation alone group

During concomitant temozolomide treatment, grade 3 or 4 neutropenia was demonstrated in 4 percent of patients, and grade 3 or 4 thrombocytopenia in 7 percent of patients

During adjuvant temozolomide therapy, 4 percent of patients had grade 3 or 4 neutropenia, and 11 percent had grade 3 or 4 thrombocytopenia

Severe infections during the radiation period occurred in 2 percent of patients in the radiotherapy alone arm and in 3 percent of patients in the temozolomide arm; severe infections during the adjuvant temozolomide period occurred in 5 percent of patients in the temozolomide arm

Author’s Conclusions

The addition of temozolomide chemotherapy to radiation for treatment of glioblastoma multiforme significantly prolongs survival, with a median increase of 2.5 months and a relative reduction in mortality of 37 percent.

There was a clinically meaningful increase (by factor of 2.5) in the 2-year survival rate among patients treated with both radiation and temozolomide.

The outcome for patients in the control arm compares favorably with earlier trials.